The present invention relates to the use of a histone deacetylase (HDAC) inhibitor or in conjunction with other agents to treat, prevent or reduce the risk of joint destruction in a subject who suffers from a joint or musculoskeletal disease by inhibiting degradation and resorption of cartilage and bone in the joint.
The development of joint destruction is usually associated with spondyloarthropathy, rheumatoid arthritis, degenerative joint disease, gout, infection, cancer, or trauma.
The spondyloarthropathy family consists of undifferentiated spondyloarthropathy, ankylosing spondylitis, juvenile onset ankylosing spondylitis, reactive arthritis, Reiter's syndrome, psoriatic arthritis, and spondyloarthropathy associated with Crohn's disease and ulcerative colitis. Distinctive features of spondyloarthropathy include asymmetric arthritis, enthesitis, genital and skin lesions, eye and bowel inflammation, and association with preceding or ongoing infectious disorders, and a strong association with human leukocyte antigen (HLA) B27. The peripheral arthritis in spondyloarthropathy is of acute onset and predominantly involves the lower extremities, especially the knees, ankles, and feet. It is typically asymmetrical and often affects only one to three joints. Sausage digits (dactylitis), sacroilitis, and spine enthesopathy are diagnostic of spondyloarthropathy. The real cause of spondyloarthropathy remains unknown. The other destructive arthropathy that needs to be distinguished from spondyloarthropathy is rheumatoid arthritis that is an autoimmune disease. Symmetrical polyarthritis of the small joints is characteristic of rheumatoid arthritis. Although the etiology of spondyloarthropathy is different from that of rheumatoid arthritis, the major pathology of the affected joints consists of in common inflammation of the synovial and extrasynovial structures such as the tendons and ligaments, inflammatory cell infiltration around joint soft tissues, production of proinflammatory mediators and enzymes from macrophages, monocytes and fibroblasts, synovial cell proliferation, and degradation and resorption of cartilage and bone, which all contribute to the destruction of the joint structure. Joint destruction occurs at the site of insertion of joint capsule, ligaments or tendons. Since the area is highly vascular, it is susceptible to bacterial invasion and antigen deposition.
To date, the current available therapies all aim at suppressing the acute exacerbation of joint inflammation and pain, but only to suppress the inflammatory or immune reaction is still not enough to stop the chronic process of the cartilage and bone degradation and resorption that results in joint destruction (Lee, D M., et al., Lancet 358: 903-911, 2001). The natural course of spondyloarthropathy and rheumatoid arthritis is one of periods of exacerbation and remission for life, and fatalities are usually due to the iatrogenic effects of therapy, such as gastrointestinal bleeding related to long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) and infection or hepatorenal toxicity associated with chronic use of steroids, immunosuppressive agents, and other disease-modifying antirheumatoid drugs (DMARDs). Although clinical trials that neutralize the major pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), by injection of either antibodies against TNF-α or soluble TNF-α receptors have produced some therapeutic anti-inflammatory effects, the major concerns are that the treatment must be administrated continually, the duration of efficacy appears to decrease with repeated doses, cessation may be associated with an increase in disease activity, the long-term usage increases the opportunity of infection, and the process of joint destruction is not stopped (Moreland, L W., et al., N. Engl. J. Med. 337: 41-147, 1997). Thus, there is an urgent need for effective therapies for preventing joint destruction and maintaining functional status.